Harnessing Cell–Biomaterial Interactions for Osteochondral Tissue Regeneration - Tissue Engineering: Cell-Surface Interactions for Tissue Culture - page 92

Although many in vitro studies have demonstrated that incorporation of growth
factor within various cartilage scaffolds enhances chondrogenesis of progenitor
cell populations and results in minor improvement after subcutaneous implantation
in vivo, functional in vivo tissue regeneration in an articular cartilage surface
remains a challenge. Some of the studies have shown only partial repair of car-
tilage defects and a minor level of improvement. Dual growth factor delivery using
a bilayer osteochondral hydrogel was also investigated to demonstrate the inter-
action of growth factors in cartilage repair [ 159 ]. In this study, GMPs with TGF-
b 1 , IGF-1, and both of them were incorporated in a chondral (top) layer of OPF
hydrogels and the gels were implanted in rabbits. In vivo analysis indicated that
single IGF-1 delivery showed minor chondral repair with GAG and cell content of
the cartilage compared to other groups, whereas single TGF-b 1 and dual delivery
did not show any improved tissue repair. A lack of any synergistic effect of dual
growth factor delivery suggests the complexity of the dynamic process of cartilage
repair and the existence of other parameters to investigate beyond a simple
combination of growth factors.
In addition to growth factor delivery, functional remodeling of osteochondral
tissue by MSC delivery remains a target for investigation. Despite various in vitro
studies that indicate successful chondrogenic differentiation of encapsulated MSC
populations in hydrogels with the aid of exogenous growth factor delivery, in vivo
cartilage regeneration with complete cartilage repair remains a challenge. Rabbit
MSCs in OPF hydrogels with or without TGF-b 1 incorporation did not show any
significant improvement in cartilage tissue regeneration [ 212 ]. Both reduced car-
tilage thickness and improved surface regularity were observed with MSC-loaded
gels. It might be hypothesized that faster subchondral bone formation in OPF/MSC
groups provided sufficient mechanical support to the articular surface region and
resulted in smoother articular surfaces. A smoother surface could also be obtained
by the participation of implanted MSCs in cartilaginous matrix secretion and
remodeling. A similar MSC/growth factor delivery in a rabbit in vivo model using
a composite hydrogel made from the self-assembling peptide sequences (RADA) 4
and (KLDL) 3 showed inconsistent results with in vitro chondrogenesis and
chondrocyte phenotypes [ 213 ]. Neither the addition of dexamethasone as well as
the chondrogenic growth factors TGF-b 1 and IGF-1 nor the combinational
incorporation of these growth factors and bone-marrow-derived MSCs in a
hydrogel led to any beneficial effect on cartilage repair. Fibrous tissue formation
was even observed in the MSC/growth factor/hydrogel group. This study dem-
onstrated a possibility to direct a single stem cell population to different zonal
phenotypes within a 3D structure with multiple layers.
Other in vivo studies using tricopolymer scaffolds with gelatin, chondroitin
6-sulfate, and sodium hyaluronate demonstrated TGF-b 1 release could help
articular cartilage repair in the full-thickness defect (4 mm in diameter and 3 mm
in thickness) in rabbits [ 214 , 215 ]. An amount of 0.8 ng of TGF-b 1 released from
embedded GMPs induced chondrogenic differentiation of autologous MSCs loa-
ded onto scaffolds [ 214 ]. Histological observation and semiquantitative scoring
data indicated that a controlled TGF-b 1 release using GMPs might be superior to